Methodology, results and quality of clinical trials of

Age and Ageing 1998; 27: 161 -179

Methodology, results and quality of clinical trials of tacrine in the treatment of Alzheimer's disease: a systematic review of the literature JESUS L6PEZ ARRIETA, FERNANDO RODRIGUEZ ARTALEJO 1

Department of Geriatrics, Cantoblanco Hospital, Madrid, Spain 1 Departamento de Medicina Preventiva y Salud Publica, UnK/ersidad del Pai's Vasco, Avenida de la Universidad 7, 01006 Vrtoria-Gasteiz, Spain Address correspondence to: F. Rodriguez Artalejo. Fax (+34) 45 130756

Abstract

Keywords: Alzheimer's disease, clinical trials, meta-analysis, systematic review, tacrine

Introduction Alzheimer's disease (AD) ranks among the principal public health problems confronting developed countries [ 1, 2]. Cholinergic deficiency is one of the main defects found in the brains of such patients and correlates with poor performance in cognitive tests [3, 4], although other mediators of neurotransmission have also been linked to AD physiopathology [5-10].

This finding led to the hypothesis that enhancing the cholinergic function of the central nervous system could slow the mental deterioration associated with the disease [12, 13]. An initial AD treatment strategy was thus based on administration of choline, but clinical studies failed to demonstrate its efficacy [14]. This was followed by studies of muscarinic agonists, such as bethanechol, arecoline and oxotremorine, but adverse effects and low selectivity for the central 161

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Objective: to review systematically the methodology, results and quality of clinical trials of tacrine in the treatment of Alzheimer's disease (AD). Methods: trials included were those conducted on AD patients, aged 40 years or over, assigned to tacrine- or placebo-based treatment. Studies were identified via the Cochrane Collaboration and MEDLJNE databases. Trialselection and data-extraction were carried out separately by two reviewers working independently. Any differences of opinion that arose were resolved by discussion. Results: we identified 49 trials published in the period 1 January 1981 -1 May 1997. Of these, 21 were randomized controlled trials, eight parallel-group and 13 cross-over type. In the random trials, tacrine dosage ranged from 25 to 200 mg/day, with a duration of 3-36 weeks. In all, 3555 patients with mild to moderate AD started treatment and 1149 failed to complete the course (mean 334% patients per trial). Over 80% of patient withdrawals were tacrinerelated. Adverse events affected a mean of 59% patients per trial (range 34-90%), mainly in the form of cholinergic manifestations (mean 30.2%, range 5-62%) and transaminase elevations (mean 28.6%, range 0-53%). Adverse events were more frequent at doses of s 100 mg/day and disappeared on discontinuation of tacrine treatment. Just over 20% of patients given tacrine experienced improvements in cognitive function (3-4 points in Alzheimer's Disease Assessment Scale cognitive subscale and 2-3 points in Mini-Mental State Examination) and in functional ability at 3-6 months of treatment. No study gave a description of concealment of the randomization sequence or the success of the double-blind procedure. Conclusions: tacrine shows a modest degree of efficacy among a small proportion of patients with mild to moderate AD, yet has important adverse effects which limit its clinical usefulness. It is not known which AD patient subgroup could benefit from the treatment. Information on the long-term effects of tacrine (over periods exceeding 7 months) and its effects on quality of life, patient institutionalization and mortality and patient burden on caregivers is inadequate.

J. Lopez Arrieta et al. nervous system limited their clinical use [15]. Lastly, cholinesterase inhibitors were used in order to augment the availability of acetylcholine in neuron receptors. Among these drugs is tacrine (tetrahydroaminoacridine). This aminoacridine acts on the central nervous system in a manner that is both complex and diverse: its known pharmacological actions include longer lasting cholinesterase inhibition than physostigmine and restoration of nicotinic receptors in AD-affected brains [16-19]. Reviews of clinical trials help obtain clear scientific evidence on the benefits, risks and costs of any given therapeutic intervention and are a tool of evidencebased medicine [20]. Narrative reviews have been published describing trials of drugs, including tacrine, for the treatment of AD [21-29]. The chief advantages of systematic as opposed to narrative reviews are the lower probability and magnitude of biases along with greater repeatability [30, 31]. Accordingly, the aim of this study is to review systematically the methodological characteristics, results and quality of trials of tacrine in the treatment of AD.

Materials and methods Study-inclusion criteria

Trials included were those conducted on AD patients, aged 40 years or over, assigned to tacrine- or placebobased treatment. Trial participants were selected on the basis of the degree of probability of the diagnosis of AD, as indicated by National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDSADRDA) criteria [32], and the degree of severity, as indicated by Diagnostic and Statistical Manual of Mental Disorders, third edition (DSM-III-R) criteria [33]- Information on tacrine efficacy was rated by one of the following types of scales: cognitive function, behavioural, functional ability, global impression of clinical change and global scales of mental deterioration. Study-search strategy

Studies were identified in the following electronic databases: the Cochrane Library (which includes the Cochrane Database of Systematic Reviews, the Cochrane Controlled Trials Register, the Cochrane Review Methodology Database and the York Database of Abstracts of Reviews of Effectiveness) and MEDLINE, for the period 1 January 1980-1 May 1997, using the search strategy proposed by Dickersin et al [34]. Extraction and presentation of data

Selection of trials for systematic review and data extraction purposes was carried out separately by two 162

Results We located 49 publications on the efficacy of tacrine in the treatment of AD, published in the period 198119% [36-84]. Of these, one was a summary of a communication delivered to a congress [74], three were chapters of a book [39, 40, 45] and the remainder were papers included in MEDLINE. Of the 49 publications, 22 corresponded to nonrandomized and/or open clinical trials and the remaining 27 reported 18 double-blind, randomized clinical trials. To identify the most appropriate tacrine dosage, three of the 18 random trials included titration phases with randomized, double-blind, treatment allocation. These trials—reported by Forette et al. [74-75], by Davis et al [76-77] and Foster et al. [84]—were therefore deemed to be studies in their own right, independent of the main study, thereby bringing the figure of random trials in this review to 21. The methodological characteristics and results of the 22 non-randomized and/or open trials are summarized in Table 1. The first trials were notable for their smaller sample size and the fact that tacrine-treatment dosage and duration were variable, ranging from single doses to 9 weeks of treatment. 1990 signalled the commencement of longer studies. The follow-up phases of random trials of tacrine were found among these studies, -which also included mortality or degree of institutionalization as outcome variables [57]. All trials used psychometric instruments to rate patients' mental function. Furthermore, in six trials, brain function techniques—positron emission tomography and single


reviewers (J.LA. and F.R.A.) working independently. Where differences of opinion arose, these were resolved by discussion between the two. Study reporting quality was assessed according to guidelines laid down by the Standards of Reporting Trials Group [35]. These guidelines list the information to be provided in the publication of a random clinical trial and are useful for evaluating the quality of the reporting but not that of the study per se. Overall scores were obtained by totalling the points for 32 items, grouped within the following areas: description of the allocation of participants to each treatment; description of the blinding of the intervention and whether this proved successful; description of subject follow-up and possible losses to follow-up; and description of the statistical analysis in the Methods and Results sections of the paper. The presence of each piece of information is awarded a score of 1, and its absence 0, so the maximum possible score for any paper is 32. Total scores for the paper and subscores for each of its sections are provided as absolutes and as a percentage of the possible maximum. Due to the heterogeneity of trial methods and the low number of studies published, no statistical synthesis of study results has been drawn up.

Tacrine and the treatment of Alzheimer's disease The most widely used functional scales were Lawton's [87, 88], particularly the instrumental activities of daily living scale and physical self-maintenance scale. General impression tests were used to grade assessor-based subjective aspect of improvement, with the clinician's global impression of change [89] being most in evidence. The global scale of intellectual deterioration most widely favoured was the total score yielded by ADAS [86] rating (Table 4). Only seven studies [69-73, 74-75, 78, 80, 82-84] specified the primary and secondary assessment variables at the outset of the trial. The results on tacrine efficacy in the 21 random trials are summarized in Table 5. In 12 trials, tacrine produced statistically significant improvement (jP < 0.05) in one or more outcome variable, infivetrials the drug led to non-significant improvement and in the remainder scarcely any difference was found between tacrine and placebo. The improvement was in cognitive variables in 12 instances and it was in overall ratings in seven. Instruments of functional ability and global clinical impression ratings showed improvements in three trials each and in only one case did tacrine show efficacy in a behavioural scale. Bearing in mind that of the subjects exposed to tacrine, 24.4% discontinued the treatment and 50.2% manifested adverse effects which generally forced them to reduce the dosage, only a litde over 20% of patients initially treated with tacrine achieved some clinical benefit as against the placebo. In line with Schneider's classification [20], random trials were divided according to sample size into small [58-61, 64-68, 79] (having under 50 participants) and large [62, 63, 69-78, 80-84] (having over 50 participants). The seven small trials were carried out earlier and all but one had a cross-over design. Of the seven, four showed some significant difference (P < 0.05) in favour of tacrine and three yielded negative results. Of the large-scale trials, half were parallel and all were carried out more recently. The results in 12 of these 14 showed clinical improvements attributable to tacrine. The reporting quality of the 21 random trials is shown in Table 6. No study gave a description of the concealment of the randomization sequence or the success of the double-blind procedure. Over 50% of the relevant information was reported only for the following areas: coverage of follow-up and statistical analyses in the Results section of the paper (Table 6). Cross-over random trials supplied 30.7% and parallel-group random trials 40.2% of all relevant information. The study with the best reporting quality was that by Knapp et al. [82], which supplied 50% of the relevant information. Discussion This systematic review has pinpointed three stages in clinical research on tacrine in AD. The first stage

163


photon computed tomography imaging [48-50, 52, 55, 56]—were employed, in four trials the electroencephalographic register was studied [44-47] and in two, indirect methods were used to evaluate the cholinergic effect of tacrine [43, 51]. In seven studies, lecithin was associated with tacrine [37, 39, 41, 42, 46-48]. In all the open studies there was improvement in some of the variables measured; only in the studies conducted by Summers et al [36], Kaye et al [37], Gauthier et al. [39, 41], Alhainen et al. [43] and Knopman et al. [57] did such improvement attain statistical significance, although, on occasion, discontinuation of tacrine led to a reversal to the baseline situation [39, 41]. In seven trials, adverse events were described for almost 60% (19-80%) of subjects treated with tacrine [36, 38-42, 54]. Table 2 summarizes the design, treatment characteristics and patient-enrolment criteria in the 21 random clinical trials of tacrine in AD. Of these, eight were parallel and 13 cross-over in design. Tacrine dosage ranged from 25 to 200mg/day. Duration of treatment ranged from 3 to 36 weeks, with a mean ± standard deviation of 9.3 ± 8.6 weeks (6.53 ± 3.8 weeks in the cross-over and 13.9 ±12.3 weeks in the parallel random trials). Only two studies [78, 82] used a preestablished tacrine dosage; the remaining trials included a preliminary titration phase. Mean age of participants was 68.9 years: 67.6 years in the cross-over studies and 70.7 years in the parallel-group random trials. In 17 random trials, NINCDS-ADRDA criteria were used for diagnosis of AD among participants and in seven random trials DSM-HI-R criteria were used to assess severity of mental deterioration. Subject enrolment was based on diagnosis of probable AD of mild to moderate severity. hi all, 3555 patients were enrolled. Parallel-group random trials had a larger sample size, with 2244 patients enrolled versus 1424 in the cross-over random trials (Table 2). A total of 1149 subjects failed to complete the trial, yielding a mean of 33-4% patients per trial. Of these, 1116 (97%) patients received treatment with tacrine. Adverse events, generally in the form of cholinergic manifestations (digestive symptoms, sweating) or serum transaminase elevations exceeding three times the upper limit of normal, appeared in 59-3% of individuals; 30.2% suffered some type of cholinergic symptom and 28.6% showed hepatotoxicity (Table 3). Adverse events were the chief reason for patient withdrawal. The 21 random trials employed 157 outcome variables, with 3-31 used per trial, except for the Forette et al. [74-75] and Davis et al [74, 75] titration phases where only the Mini-Mental State Examination (MMSE) [85] was used. Among the instruments used for studying intellectual functions, the MMSE proved to be the most frequent (Table 4). Of the behavioural scales, the most common was the Alzheimer's Disease Assessment Scale (ADAS) non cognitive subscale [86].

Canada

Sweden

Canada

UK

Gauthierefai [39]

Nybackefa/. [40]

Gzuthier et aL [41]

Forsyth et al. [42] 1989 8

1989 52

1988 10

1988 51

9 weeks

8 weeks

5 weeks

8 weeks

1-7 months

1988 6

Austria

Dai-Bianco et al. [38]

16 h in three doses

USA

Kaye et al. [37]

Dose/day

Lecithin/ day

75-150 mg

25-100 mg

25-200 mg

50-100 mg

i.v.; 15-60 mga

90 mg (total)

10.8 gb

3.4 g

7.2 g

60g

Single parenterai 0.25-1.25 mg/kg dose in 60 s

Duration

1982 10

1981 12

USA

Summers et al. [36]

n

Year

Country

Reference

Tacrine treatment

Table I. Non-randomized and/or open clinical trials of tacrine in Alzheimer's disease

Nine out of 12 patients improved, four markedly so, in OTand NLT. Improvement was inversely proportional to severity of dementia, statistically significant in four patients with mild dementia (P < 0.01). At dosages of i l mg/kg, six individuals complained of cholinergic effects A comparison run on four types of randomi2ed intervention: placebo, THA, LE, THA/LE. In the THA/LE group, patients with highest WMQ scores registered greatest SLT-based improvement. In the four patients with severe AD there was no type of Improvement. The two moderate AD patients achieved clear improvement in associative ability, language and global impression of change. In two cases THA was discontinued owing to dizziness, pruritus or accommodation disorders and two patients registered transaminase elevations which subsequendy returned to normal levels on THA being stopped Improvement in MMSE (/>= 0.026), VWF (P = 0.025) and SRT (P= 0.007) after 4 weeks on tacrine, but returned to baseline situation 2 weeks after discontinuation of treatment. Half of subjects improved in the clock test, returning to baseline situation at 2-4 weeks after discontinuation of tacrine. Improvement also observed in RDRS-2 (f = 0.012) after 6 weeks on tacrine. Study suspended when over 30% of patients registered transaminase elevations. Statistical analyses performed on all 19 patients who completed the study. 80% of individuals suffered gastrointestinal discomfort Improvement in verbal ability and memory in 50% of individuals; 70% presented with cholinergic effects and one patient registered transaminase elevation, leading to THA being discontinued Improvement in MMSE (i> = 0.01), 3MS (P < 0.01), the ADL section of the RDRS-2 (P = 0.02) at 4 weeks on tacrine and return to the basal situation at 2 weeks after discontinuation of treatment. Behavioural AD deteriorated significantly (P= 0.01). Two patients reported transaminase elevations exceeding three times the upper limit of normal and eight (17%) cholinergic effects Statistically non-significant improvement in neuropsychological and behavioural assessment. All patients registered transaminase elevations, in one case exceeding three times the upper limit of normal; five patients developed cholinergic effects, responsible for patient withdrawal in three cases.

Results/comments Downloaded from ageing.oxfordjournals.org by guest on July 12, 2011

Q

N

1992 3 1993 22

Finland

Finland

USA

Holland USA UK

Sweden Finland

Sweden

Alhainen et al [44]

Alhainen et al [45]

Perryman & Fitten [46] van Gool et al [47]

Cohen et al [48]

O'Brien et al. [49]

Nordberg et al. [50]

Alhainen et at [51]

Nordberg [52] 1993 5

1992 9

1992 6

1991 8 1991 12

1991 18

1991 14

1991 20

Finland

n

Alhainen et al [43]

Year

Country

Reference

Table I. (Continued)

43-65 weeks

4 weeks

13 weeks

80-160 mg

100 mg

80 mg

50-125 mg

75-200 mg

1 week 12 weeks

75-200 mg 75-100 mg

£100 mg

£100 mg

£100 mg

Dose/day

4 weeks 12 weeks

4 weeks

7 weeks

4 weeks

Duration

Tacrine treatment

30 g

10 g

9g

Lecithin/ day

11 out of 20 patients deemed responders (&3 points in the MMSE). In these cases, improvement was clearly significant (range 17.4 ± 1.4 to 21.5 ± 1.5; P100 mg/day, 62.2% being cholinergic In nature. 46% of those exposed to THA registered reversible transaminase elevations. In 21% of these, elevation exceeded three times the upper limit of normal. During the placebo stage, 11 patients reported adverse events (12%)

The single patient withdrawal was due to transaminase elevation. Four subjects in the THA group also registered the same elevation which returned to normal on termination of the trial; two of these patients complained of digestive disorders

Of seven patient withdrawals during the titration phase, one was ascribablc to hepatotoxicity and another to undesirable cholinergic events; 13 patients registered transaminase elevations and two suffered cholinergic effects

Comments

Liver


ft

Si

3i ft

2. a

N"

8,

P

3

o.

a v

I

Tacrine

Trial 2

Trial 2

Davis el aL [76, 77] Trial 1 113/632(17.8)

75/215 04.8)

53/103(51.4)22/112(19.6)

23/122(18.8)

8/280(13.5)

Total

102/632(16.1) 1/632(1.7)

?

Placebo

No. (and %) of withdrawals

Forette et aL [74, 75] Trial 1 ?

Reference

Table 3. (Continued)

38/103 06.9)

277/632(43.8)

48/68(70.5)

9/280(35.3)

Tacrine

15/103(14.5)

100/632(15.8)

17/54 01.5)

30/280(10.7)

Placebo

No. (and %) of adverse events By treatment

377/632(60.0)

65/122(53.2)

129/280(46.1)

Total

Uver

218/632 04.5) 59/632(9.3)

106/280 07.9) 84/264 01.9)

ChoUnergic

By type


42% of THA patients had transaminase elevations, in 21% of cases exceeding three times the upper limit of normal. Adverse events were more frequent in women than in men: 67% vs 32%. There were 113 patient withdrawals (18%), with 66 (10%) of these being due to hepatotoxldry. Eighty out of a total of 113 patient withdrawals occurred during the titration phase, 11 during the placebo stage, 12 during the comparative double-blind stage and 10 during the open maintenance stage with THA. In the lastmentioned Instance, there were 16 patients (8%) with hepatotoxidty and 54 patients (27%) manifesting cholinergic symptoms

There were 36 patient withdrawals owing to adverse effects (13%), with 19of these being due to hepatotoxidty (17%). Eighty-four individuals of the 264 exposed to THA 02%) showed transaminase elevations, with 11% of these exceeding three times the upper limit of normal Adverse effects during the tltration and comparison phases appeared in 38 and 39% of patients, respectively

Comments

n

•o N >

18/53 04.0)

Maltbyef al [81]

3/18(16.6)

10/79(12.6)

0/17

265/479(55.3)20/184(10.9)

26/79 02.9)

Wilcock etal [80]

Knapp et al [82]

0/17

Minthon et al [79]

193/310(62.2)25/158(15.8)

Farlow et al [78]

Placebo

Tacrine


Reference


285/663(43 0)

21/53 09.6)

36/79(45.5)

0/17

218/468(46.6)

Total Placebo

2/18(11.1)

0/17

450/479(94.0) 150/184(81.5)

16/53 00.2)

9/17 (52.9)

184/310(59.3) 23/158(14.5)

Tacrine

By treatment

No. (and %) of adverse events

600/663(90.5)

18/53 04)

9/17 (52.9)

Comments 43% (split proportionally between men and women) of THA patients had transamlnase elevations, with 25 % of elevations exceeding three times and 7%, 10 times the upper limit of normal Nine subjects suffered hepatotoxidty yet only three needed to reduce the THA dosage The principal reason for withdrawal was transaminasc elevation exceeding three times the upper limit of normal in 20 patients (25%) during the active phase, 17 of whom also suffered cholinergic symptoms. Four patient withdrawals were ascribable to adverse events During the tltratlon phase there were 12 patient withdrawals, six due to transaminase elevations exceeding three times the upper limit of normal and one to cholinergic effects. Of the six patients in the THA group who withdrew during the comparative double-blind stage, three did so owing to a rise in transaminase exceeding three times the upper limit of normal

Liver 202/468(43.2)

16/53 (3O.2)b

20/79 (25.3)

9/17 (52.9)

79/479 (l6.5)b 133/479 (27.8)b The chief reason for withdrawal in the THA group was transaminase elevation: 133 subjects (28%); 98 of these tolerated rcchallenge with THA during the open phase. Seventy-eight patients (16%), 21 of whom were on a tacrine dosage of 160 mg/day, withdrew due to cholinergic effects

17/79(21.5)

?

207/468(44 2) 87/310(28.1)

Total

By type Cholinergic Downloaded from ageing.oxfordjournals.org by guest on July 12, 2011

a

!

3i*

Q.

3-

A

2.

N

A

3 ft

ft ft-

26/148(17.5) ? 26/148 (17.5)

10/122 (8.2)

170/435 (39)

?

GRS, Geriatric rating scale; THA, tacrine; WA1S, Weschler adult Intelligence scale; ?, insufficient data available. "Overlap between THA and placebo treatment groups. b Data refer to withdrawals rather than the total exposed.

Trial 2

Foster e/oi [84] Trial 1

69/154 (44.8)

12/70(17. l)

22/76 29.0%

47/78 (60.3)

6/76(79)

17/78(21.8)

Wood et aL [83] 23/154(14.9)

Cholinergic

Total

Placebo

Tacrine

Placebo

Tacrine

Reference Total

By type

By treatment

No. (and %) of adverse events



b

170/435 09)

31/70(44.3)

Uver Downloaded from ageing.oxfordjournals.org by guest on July 12, 2011

170 of the 435 patients with ALT measurements at screening had transaminase elevations; 93 (21%) exceeding three times the upper limit of normal. The incidence of transaminase elevations was highest among female patients (45% female vs 30% male)

Twelve of the 16 patients who withdrew due to cholinergic effects were in the THA group. Six withdrew owing to transaminase elevations exceeding twice the upper limit of normal. 60% registered transaminase elevations, with 22% exceeding twice the upper limit of normal

Comments

a

ft'

•o ft N

Tacrine and the treatment of Alzheimer's disease Table 4. Assessment scales in randomized clinical trials of tacrine in Alzheimer's disease Type

n

Cognitive MMSE Digit span ADAS, cognitive subscale Benton visual retention test Kendrick digit copying task Weschler adult intelligence scale Verbal word fluency CAMDEX, cognitive section WMS Modified MMSE Names learning test Orientation test Trail making test Kendrick object learning test Other

4 3 3 2 2 2 2 2 2 2 2 2 31

9 2 2

5 5 8

6 4

3 3 5 7

3 3 3 9

ADAS, Alzheimer's disease assessment scale; MMSE, mini-mental state examination; WMS, Wechsler memory scale.

comprises trials conducted in the 1980s and early 1990s, with small sample sizes, non-randomized and/or open designs and relatively small doses of tacrine over short periods of time [36-45] (Table 1). These studies generated excessively optimistic expectations as to the benefits of tacrine. Their chief contribution was to demonstrate the hepatotoxic effects of tacrine, even at low doses, and to stimulate research in this field. The second stage was of trials that were more methodologically sound, characterized by randomized allocation of treatment and conducted in the second half of the 1980s and in the 1990s (Tables 2-6) [5884]. The considerable number of scales used in the

173


Behavioural ADAS, non-cognitive subscale Behave-AD Geriatric depression scale Other Clinical global impression Clinician's global impression of change Other Functional ability Instrumental activities of daily living Physical self-maintenance scale Blessed-Roth scale Progressive deterioration scale Other Global mental deterioration ADAS, total score Rapid disability rating scale Global deterioration scale Hierarchic dementia scale Other

16 5

random trials in order to rate response to treatment (Table 4) suggests that none proved altogether satisfactory [90]. Moreover, there are serious shortcomings in the reporting of the results of these studies. Particularly noteworthy is the lack of information on the concealment of the randomization sequence and the success of the double-blind procedure, since there is empirical evidence to show that this can spuriously magnify the effect estimators [91, 92]. Among these 'second-stage' random trials, the most informative are those by Farlow et al [78] and Knapp et al [82], together with the comparative double-blind phases of the studies by Forette et al [74,75] and Davis et al [76, 77]. These studies have a large sample size, thereby enabling more precise measurement of the effect of tacrine, and a parallel design, which makes it possible to control for time-dependent confounders. This is important as the clinical course of AD varies widely, with periods of cognitive stabilization of up to 2 years [93]. Inclusion criteria are clear (DSM-IH-R and NTNCDS-ADRDA), affording relative assurance on the diagnosis and homogeneity of patients studied. In most cases the ADAS scale was used as the principal variable of assessment, this scale being one of the most reliable having been drawn up to evaluate the therapeutic effects of drugs in AD [94]. Furthermore, these studies report the relationship between tacrine dosage and the drug's efficacy and toxicity. Finally, they earned some of the highest ratings for reporting quality (Table 6). The third stage takes in studies that provided continued follow-up for some 'second-stage' random trials and were carried out in the period 1993-96 [5257] (Table 1). They supply information on the longterm effects (safety) of tacrine and, in certain cases, on its effect on the quality of life, institutionalization and mortality of AD patients [57]. The chief limitation on these studies lies in their lack of a control group (ideally composed of untreated AD patients), with the result that they have a limited capacity for drawing inferences on clinical usefulness. 'Second-stage' random trials have shown that tacrine has a modest dose-dependent efficacy in cases of mild to moderate AD. The greatest benefits are obtained at doses of 120-160 mg/day [82], although it is possible to obtain certain benefits at a dosage of 80 mg/day, thereby ameliorating the adverse effects of treatment [78]. The benefit yielded by tacrine is particularly evident in cognitive function, functional ability and global scales of mental deterioration. The clinical relevance of benefit may be inferred by comparison with the usual evolution of cognitive function in AD. The MMSE falls by 3 points every 6-12 months [95] and the cognitive component of the ADAS rises by 7 points per year [96] in mild to moderate AD in the absence of treatment. It is therefore estimated that tacrine, at a dosage of 80-160 mg/day over a period of 6-30 weeks, slows the course of AD by approximately 6 months [71, 74-76, 78, 82]. This benefit is

J. Lopez Arrieta et al. Table 5. Randomized clinical trials of tacrine in Alzheimer's disease: tacrine efficacy Reference Summers et al [58] Davies et al [59, 60] Fitten et al. [61]

Gauthier et al. [62]

Chatellier et al [63] Ahhnetal [64-66] Molloy etal. [67]

Eaggeretal [69-73] Forette et al [74, 75] Trial 1

Trial 2

Davis et al [76, 77] Group 1

Group 2

174

Total ADAS score at 2 weeks showed a mean improvement of 3-4 points (decline in absolute score) in the group at a tacrine dosage of 40 mg/day and 2.9 points in the placebo group (a difference between the two groups of -0.3; P = 0.76). There were no differences in the ADASnc. A carry-over effect was observed in patients who had been administered tacrine prior to the placebo ADASc improvement (P= 0.02). 39% of subjects in the THA group improved by at least 2 points in the ADASc vs 21% of the placebo group, with a dose-dependent effect being observed (46% in the THA-80 group and 20% in the THA-40 group). No significant difference in CGIC scores in the groups used for comparison purposes. The difference of -0.6 points in favour of the THA group in ADASt was not significant (P = 0.64). No statistically significant differences in ADASnc, MMSE, PDS, IADL and PRM ratings The first 2 weeks of the titration phase constituted a parallel study comparing tacrine at a dosage of 40 mg against placebo. Mean decline of 2.5 points in ADAS total score in the tacrine group vs only 1 point of mean decline in the placebo group (P — 0.002) 2.4-point improvement on the ADASc scale (P < 0.001). No significant improvement found on the CGIC scale. Improvement of 2.4 points in the PDS quality of life scale (P— 0.04). The change in the MMSE score favoured the THA group, though the difference foiled to attain statistical significance. Patients reverted to the baseline situation at 6 weeks after discontinuation of treatment. The magnitude of the effect was approximately computed by inferring the expected decline in ADASt (7 points per year): 5-month delay in cognitive deterioration; approx. three extra words recalled from a list 10 or successful performance of three extra instructions vs the control group.


Weinstein et al [68]

Results/comments In the 14 patients that completed the blind phase, THA yielded improvement in the GA (P = 0.003), OT (P = 0.004), NIT (P = 0.001), ADS (0.003) scales and in GSAD stages 2, 3 and 4 (P < 0.05). This positive effect held during the follow-up phase Improvement in one out of 10 memory tests (KOLT) (P= 0.025). Significant decline in two out of 10 memory tests at 3-month follow-up Of the six patients who initiated and completed the protocol, only one showed clinically relevant improvement (neuropsychological tests, clinical impression of change). A further two improved in at least one cognitive test during treatment with tacrine. There were no differences in the MMSE Of the five result variables, only the MMSE improved (P— 0.03) after 4 weeks with tacrine in a dose of 85 mg/day. Patients returned to the baseline situation at 2-4 weeks after discontinuation of treatment There were no statistically significant differences in MMSE or SGRS scores. However, 10% of patients registered a 4-point improvement in the MMSE There was an improvement in the emotional state as evaluated by the GRS (P < 0.05) and the WMS information test (P < 0.05) No effect was observed as regards cognitive functions, behaviour and ADL, nor was any specific patient subgroup pin-pointed as a responder group No improvement was observed in the dependent variables that measure mental performance, functional ability and behavioural change. Improvement in the AMTS (P < 0.0001) and MMSE (P < 0.0001). The improvement was seen in the MMSE in 45% of tacrine — vs only 11% of placebo-patients. No significant difference was found in IADL

Tacrine and the treatment of Alzheimer's disease Table 5. (Continued) Results/comments

Farlow et al [78]

Comparison of tacrine at a dosage of 80 mg/day vs placebo led to an improvement in ADASc (JP= 0.15), physician-based CGIC (P = 0.016) and caregiver-based CGIC (P = 0.028). Improvement of 4 points seen in the ADASc in 51% of patients and 7 or more points in 27% of patients in the THA 80 mg group vs only 18% in the placebo group. Tacrine efficacy proved to be dose-dependent. No improvement in secondary dependent variables: PDS and MMSE. A difference in ADASt of 3.6 between the THA 80 mg and placebo groups at 12 weeks, induced the authors to conclude that there was a benefit of a 6-month delay in the disease No improvement in clinical grading, iatrogenic assessment, clinical impression of change and psychometric scales, EEG and cerebral blood flow Improvement, albeit not statistically significant, in all primary result variables. Five out of the seven secondary variables showed THA-related benefit, in two cases (KOLT and CAMCOG) attaining statistical significance (P=0.02 and P= 0.004 respectively). 23% of patients registered an improvement of 3 points in the MMSE (equivalent to a 6-12 month delay in AD) vs 5% during the placebo phase No improvement in the result variables after 9 months of treatment, except in instrumental ADL (P= 0.04) and the countdown test (P = 0.035) Dose-proportional improvement (P < 0.05) in the following outcome variables, ADASc, ADASt, CIBI, MMSE and GDS. The effects were relevant at week 18 in terms of the ADASc and CIBI at a dosage of 120 mg/day and at week 30 on these same scales and the FCCA at a dosage of 160 mg/day. Of the 42% of patients who completed the study, 40% improved by over 4 points in ADASc. Owing to the high number of withdrawals, intentto-treat analyses showed that THA is only moderately superior to placebo, 23% vs 17%, respectively Most patients in the THA group tolerated 80 mg/day and improved as against the control group in terms of the CARS and RGRS clinical impression scales (P < 0.05). Nonstatistically significant improvement in the MMSE. There was a notable variation in patient response

Minthon et al [79] Wilcockefa/. [80]

Maltbyefa/. [81] Knapp et al. [82]

Wood et al [83]

Foster et al [84] Trial 1 Trial 2

The ADASc improved (P = 0.05) with THA 80 mg/day No significant improvement detected

ADAS, Alzheimer's disease assessment scale; ADASc, Alzheimer's disease assessment scale-cognitive scale; ADASnc, Alzheimer's disease assessment scale-non cognitive scale ADASt, Alzheimer's disease assessment scale, total score; ADS, Alzheimer's deficit scale; AMTS, abbreviated mental test; ANCOVA, analysis of covariance; CAMCOG, CAMDEX, cognitive section; CGIC, clinical global impression of change; CARS, clinical global rating score; CIBI, clinician interview-based impression; AD, Alzheimer's disease; EEG, electroencephalogram; FCCA, final comprehensive consensus assessment; GA, global assessment; GSAD, global stages of Alzheimer's disease; GDS, global deterioration scale; GRS, geriatric rating scale; IADL, instrumental activities of daily living; KOLT, Kendrick object learning test; MMSE, mini-mental state examination; NLT, names learning test; OT, orientation test; PDS, progressive deterioration scale; PRM, profil de rendement mnesiquc; PSMS, physical self-maintenance scale; RDRS, rapid disability rating scale; SGRS, Stockton geriatric rating scale; THA, tacrine; WMS, Weschler memory scale.

considered clinically relevant by the US Food and Drug Administration [97], even when it represents no more than 10% of the clinical phase of the disease [98, 99]. However, the adverse effects of tacrine—both cholinergic and hepatic—mean that only one-third of all patients receive the more effective dosage levels of 160 mg/day [82]. Furthermore, at least 50% of patients on therapeutic dosages suffer adverse effects [100] and only 20% of patients treated with high doses experience the benefits of the medication, with such benefits tending to disappear a few weeks after medication is halted [39, 41]. It is, therefore, unlikely that more than

20% of patients initially treated with tacrine will benefit from the treatment. It is not known which AD patient subgroup could benefit from the treatment. Information on the longterm effects of tacrine (periods exceeding 7 months) and on its effects on quality of life, patient institutionalization and mortality and patient burden on caregivers, is inadequate. The cost-effectiveness of tacrine in AD is also unknown, although it would have to delay institutionalization by a minimum of 9 months for the treatment to be cost-effective [101]. In conclusion, tacrine shows a modest degree of

175


Reference

J. Lopez Arrieta et al. Table 6. Reporting quality of randomized clinical trials of tacrine in Alzheimer's disease Statistical analysis Participant allocation 1 1 1 1 2 1 1 2 1

Blinding

Follow-up

Methods

Results

Total

1 0 0 1 0 0 0 0 0

2

1 1 1 1

8 (25.0) 10 (31.2) 8 (25.0) 11(34.3) 15 (46.8) 8 (25.0) 10(312) 13 (40.6) 13 (40.6)

1 1 1 1 2 1 1 2

2

1 2

3 3

3 4

3 5 3 6 5 3 5 5 5

0 0

2 2

3 3

5 5

11(34.3) 11 (34.3)

2

3 3 5

5 5 5

2 2 2

0 2

2

0 0 0 0 0 0 0 0

11 (34.3) 12 (37.5) 15 (46.8) 5 (15.6) 7 (21.8) 12 (37.5) 16 (50.0) 13 (40.6)

2 2 1.42(23.6)

0 0 0.09 (0)

2 2 2.47 (61.7)

3

3 3 2

3 3

3 3 2 2

3 3 2

5

5 3

5 5 6

3 3

4 4

2.66 (38.0)

11 (34.3) 11 (34.3) 4.3(71-7) 11 (34.3)

"Percentage of the maximum possible score: assessment as per Guidelines of tbe Standards of Reporting Trials Group (1994) [35].

efficacy among a small proportion of patients with mild to moderate AD and has adverse effects which limit its clinical usefulness. However tacrine should be used as a benchmark for the evaluation of other aminoacridines such as donepezil, galantamine and metrifonate as anti-dementia drugs. The ideal drug -would have greater clinical efficacy than tacrine, a lower dosage frequency, greater safety and lower cost.

side effects or elevations in serum transaminase concentrations. Some patients with mild to moderate Alzheimer's disease show clinical benefit on tacrine but these patients cannot be identified before starting treatment.

References Acknowledgements We thank Carlos Rodriguez Pascual and Teresa Olcoz Chiva for their helpful comments on an earlier draft of the paper and Michael D. Benedict for preparing the English-language version. This study was funded in part by grant no. 96/0477 from the Fondo de Investigation Sanitaria (Health Research Fund).

Key points • This systematic review of 49 clinical trials of tacrine in Alzheimer's disease showed that one-third of patients were withdrawn from treatment. • Most withdrawals were because of cholinergic 176

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© Sam Tanner.